A clinical trial of a new vaccine against dengue fever shows progress toward fighting the most common mosquito-borne disease. The drug is less successful than hoped, but seems to be effective at preventing three of the four related viruses that cause dengue.

Dengue fever increasing

Dengue fever is endemic across the tropics, with more than 2.5 billion people in 128 countries at risk. Symptoms can range from aches and fever to circulatory failure, coma and death. Some 21,000 people die of dengue each year, and the number of cases is increasing, including outbreaks in the southeastern United States.

There is no vaccine available to prevent dengue fever. Part of the difficulty in developing one is that there are four different but related types of the disease. Those who recover from infection by one type gain lifetime immunity, but only against that type. Scott Halstead, of the Dengue Vaccine Initiative, explains that they are still at risk of infection with one of the other types.

"Dengue normally produces a short acute febrile disease, sort of a flu-like disease which ends in a rash, and when you're convalescent, you have life-long immunity to the type you've been infected with, say Type 1. But you are susceptible then to either type 2 or 3 or 4, and what we've learned is that two different infections - with say, Type 1 and Type 2 - can result in a very severe catastrophic disease called dengue hemorrhagic fever, and this occurs all over the tropical world, mostly in Asia and the American tropics," Halstead explained.

New vaccine

That is why researchers are focused on developing a so-called tetravalent vaccine, modeled on the successful yellow fever vaccine, combining weakened versions of all four types of dengue virus into a single drug.

Halstead, who was not involved in the new clinical trial, says the pharmaceutical company, Sanofi Pasteur, took a molecular approach to creating its vaccine.

"They actually spliced the gene for each of the four dengue viruses into a yellow fever backbone. So this is a combined vaccine called a chimera, combining the yellow fever replicative machinery and the dengue surface proteins," he said. "But it is a vaccine mixture of dengue 1, 2, 3 and 4."

In the first trial to determine whether a vaccine could actually prevent the disease, Sanofi's drug was tested in 4,000 school children in Thailand. The children got three doses of either the vaccine or a placebo. Spacing the shots six months apart was meant to mimic the natural immune response people develop over time. Two years later, the vaccine seemed to have protected the children against three of the four strains, but not the most common type of the virus, which accounts for about 40 percent of severe dengue cases worldwide.

But the results show that the vaccine is safe, and technologically possible.

Although Halstead and many other dengue experts expressed disappointment that Sanofi's vaccine was not more effective, they regard it as an important step forward.

"The problem is, can we use a vaccine that only protects against three? In my commentary that I wrote for The Lancet, I speculated that maybe, if you could really give enough of a three-component vaccine to stop transmission, you'd actually leave just one virus, and one virus all by itself won't cause dengue hemorrhagic fever. So a lot of the really serious problems caused by dengue viruses might be controlled with a three-component vaccine," said Halstead.

Sanofi is already testing its new vaccine in large Phase 3 trials involving more than 30,000 people in 10 countries, with results expected in 2014. A report about the Phase 2 trial, and Dr. Halstead's commentary, appear in the medical journal, The Lancet.